CD6 is a T-cell costimulatory molecule expressed on developing thymocytes and on mature T-cells. We hypothesize that a major role of CD6 is to costimulate thymocytes and mature T-cells during low functional avidity interactions with MHC/antigen complexes and to augment resistance of these cells to apoptosis. Mechanisms by which CD6 may contribute to autoimmunity include increased selection of self-reactive thymocytes, increased resistance of thymocytes and/or mature T-cells to apoptosis, and decreases in the stimulation threshold of mature T-cells to self-antigens. We will use complimentary "gain of function" and "loss of function" approaches, including mice bred either to lack or to overexpress CD6, in combination with antigen-specific TCR transgenic mice, thymic organ cultures, and specific soluble reagents which inhibit CD6/CD6 ligand interactions. Potential excesses in CD6-dependent costimulation could also occur if CD6 ligands are over-expressed during T-cell development and/or in tissues affected by autoimmunity. We have identified a new CD6 ligand that is expressed in the thymus, in skin and in synovium. We plan to clone this new CD6 ligand and to study its expression on thymic epithelium during T-cell development. Our specific aims are 1) to test the hypothesis that CD6-dependent costimulation to thymocytes increases functional avidity for AMC/antigen complexes and/or resistance to apoptosis; 2) to test the hypothesis that CD6-dependent costimulation to mature T-cells increases functional avidity and/or resistance to apoptosis; and 3) to clone the novel CD6 ligand and characterize its expression in the thymus. Our long-term goal is to understand the role of CD6 in immunity. One of the major problems in the treatment of autoimmunity is that current therapies reduce both autoimmunity and protective immunity simultaneously. We ultimately want to determine if inhibiting CD6/CD6L interactions can selectively inhibit reactivity with weaker self-antigens without compromising responses to stronger exogenous antigens that are important in innate immunity.